scholarly journals WISKOTT-ALDRICH SYNDROME (WAS) CARRIER DETECTION BY X-CHROMOSOME INACTIVATION ANALYSIS

1987 ◽  
Vol 21 (4) ◽  
pp. 313A-313A ◽  
Author(s):  
Donald B Kohn ◽  
Eric R Fearon ◽  
Jerry A Winklestein ◽  
Bert Vogelstein ◽  
R Michael Blaese
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Carrier Detection ◽  
Chromosome Inactivation ◽  
Wiskott Aldrich Syndrome

scholarly journals Case Report: Wiskott-Aldrich Syndrome Caused by Extremely Skewed X-Chromosome Inactivation in a Chinese Girl

2021 ◽  
Vol 9 ◽  
Author(s):  
Xuening Hou ◽  
Jie Sun ◽  
Chen Liu ◽  
Jihong Hao
Keyword(s):  
X Chromosome ◽  
Clinical Manifestations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Chinese Girl ◽  
Skewed X Chromosome Inactivation ◽  
Female Carriers

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of Wiskott-Aldrich syndrome protein due to WAS gene mutation, which is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high risk of autoimmune complications and hematological malignancies. Although affected males with WAS usually manifest severe symptoms, female carriers have no significant clinical manifestations. Here, we describe a Chinese girl diagnosed with WAS carrying a heterozygous missense mutation in exon 2 of the WAS gene. The patient presented with persistent thrombocytopenia with small platelets and decreased WAS protein detected by flow cytometry and western blot analysis. The methylation analysis of the HUMARA gene displayed an extremely skewed X-chromosome inactivation (SXCI) pattern, where the X-chromosomes bearing normal WAS gene were predominantly inactivated, leaving the mutant gene active. Hence, our results suggest that completely inactivating the unaffected paternal X-chromosomes may be the reason for such phenotype in this female patient. SXCI has important implications for genetic counseling of female carriers with a family history of WAS.

scholarly journals Carrier detection in the Wiskott Aldrich syndrome

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1735-1739
Author(s):  
ER Fearon ◽  
DB Kohn ◽  
JA Winkelstein ◽  
B Vogelstein ◽  
RM Blaese
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Cell Populations ◽  
Severe Thrombocytopenia ◽  
Wiskott Aldrich Syndrome ◽  
Length Polymorphisms ◽  
Methylation Patterns ◽  
Normal Controls ◽  
Restriction Fragment Length

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by immunodeficiency and severe thrombocytopenia in affected males, but no demonstrable clinical abnormalities in carrier females. Through analysis of the methylation patterns of X-linked genes that display restriction fragment length polymorphisms (RFLPs), we studied the pattern of X-chromosome inactivation in various cell populations from female relatives of patients with WAS. The peripheral blood T cells, granulocytes, and B cells of eight obligate WAS carriers were found to display specific patterns of X-chromosome inactivation clearly different from these of normal controls. Thus, carriers of WAS could be accurately identified using this analysis.

scholarly journals Atypical presentation of Wiskott-Aldrich syndrome: diagnosis in two unrelated males based on studies of maternal T cell X chromosome inactivation [see comments]

Blood ◽  
1990 ◽  
Vol 75 (12) ◽  
pp. 2369-2374 ◽  
Author(s):  
JM Puck ◽  
KA Siminovitch ◽  
M Poncz ◽  
CR Greenberg ◽  
M Rottem ◽  
...  
Keyword(s):  
T Cell ◽  
X Chromosome ◽  
Hereditary Disease ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Negative Family History ◽  
Wiskott Aldrich Syndrome ◽  
Inactivation Pattern ◽  
Skewed X Chromosome Inactivation ◽  
Cell Defect

Congenital thrombocytopenia may occur in isolation or accompanied by eczema and immunodeficiency, as part of the X-linked hereditary Wiskott- Aldrich syndrome (WAS). Because the clinical and immunologic picture of WAS is variable, particularly early in life, definite diagnosis cannot always be made in cases with a negative family history. Two unrelated males with sporadic congenital thrombocytopenia had only questionable immunologic abnormalities as infants, making them clinically indistinguishable from cases of isolated thrombocytopenia, although one developed episodic neutropenia and the other began to manifest a multisystem autoimmune disease at 2 years of age. Evaluation of X chromosome inactivation in the T cells of both patients' mothers showed each of these women to have the same highly skewed X chromosome inactivation pattern seen in carriers of typical familial WAS. A T-cell defect was subsequently directly demonstrated in the second patient, whose lymphocytes failed to proliferate to periodate and anti-CD43. Taken together, these data suggest the presence of T cell immunodeficiency consistent with WAS in these patients. Furthermore, their mothers were found to have a very high likelihood of being carriers, lending support to the diagnosis of a hereditary disease in these boys and making possible genetic prediction in other family members and subsequent pregnancies.

Wiskott–Aldrich syndrome in a female with skewed X-chromosome inactivation

2003 ◽  
Vol 31 (3) ◽  
pp. 332-337 ◽  
Author(s):  
Nuria Andreu ◽  
Núria Pujol-Moix ◽  
Luis Martinez-Lostao ◽  
Marta Oset ◽  
Eduardo Muñiz-Diaz ◽  
...  
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Wiskott Aldrich Syndrome ◽  
Skewed X Chromosome Inactivation

Wiskott-Aldrich syndrome in a female

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2763-2768 ◽  
Author(s):  
Maxim I. Lutskiy ◽  
Yoji Sasahara ◽  
Dianne M. Kenney ◽  
Fred S. Rosen ◽  
Eileen Remold-O'Donnell
Keyword(s):  
T Cells ◽  
X Chromosome ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Wild Type ◽  
Wiskott Aldrich Syndrome ◽  
Blood Mononuclear Cells ◽  
Disease Free

Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by thrombocytopenia, eczema, and various degrees of immune deficiency. Carriers of mutated WASP have nonrandom X chromosome inactivation in their blood cells and are disease-free. We report data on a 14-month-old girl with a history of WAS in her family who presented with thrombocytopenia, small platelets, and immunologic dysfunction. Sequencing of the WASP gene showed that the patient was heterozygous for the splice site mutation previously found in one of her relatives with WAS. Sequencing of all WASP exons revealed no other mutation. Levels of WASP in blood mononuclear cells were 60% of normal. Flow cytometry after intracellular staining of peripheral blood mononuclear cells with WASP monoclonal antibody revealed both WASPbright and WASPdimpopulations. X chromosome inactivation in the patient's blood cells was found to be random, demonstrating that both maternal and paternal active X chromosomes are present. These findings indicate that the female patient has a defect in the mechanisms that lead in disease-free WAS carriers to preferential survival/proliferation of cells bearing the active wild-type X chromosome. Whereas the patient's lymphocytes are skewed toward WASPbright cells, about 65% of her monocytes and the majority of her B cells (CD19+) are WASPdim. Her naive T cells (CD3+CD45RA+) include WASPbrightand WASPdim populations, but her memory T cells (CD3+CD45RA−) are all WASPbright. After activation in vitro of T cells, all cells exhibited CD3+CD45RA− phenotype and most were WASPbright with active paternal (wild-type) X chromosome, suggesting selection against the mutated WASP allele during terminal T-cell maturation/differentiation.

Combined De-Novo Mutation and Non-Random X-Chromosome Inactivation Causing Wiskott-Aldrich Syndrome in a Female with Thrombocytopenia

2013 ◽  
Vol 33 (7) ◽  
pp. 1150-1155 ◽  
Author(s):  
Boonchai Boonyawat ◽  
Santhosh Dhanraj ◽  
Fahad al Abbas ◽  
Bozana Zlateska ◽  
Eyal Grunenbaum ◽  
...  
Keyword(s):  
X Chromosome ◽  
De Novo ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
De Novo Mutation ◽  
Wiskott Aldrich Syndrome

scholarly journals Carrier detection in the Wiskott Aldrich syndrome

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1735-1739 ◽  
Author(s):  
ER Fearon ◽  
DB Kohn ◽  
JA Winkelstein ◽  
B Vogelstein ◽  
RM Blaese
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Cell Populations ◽  
Severe Thrombocytopenia ◽  
Wiskott Aldrich Syndrome ◽  
Length Polymorphisms ◽  
Methylation Patterns ◽  
Normal Controls ◽  
Restriction Fragment Length

Abstract The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by immunodeficiency and severe thrombocytopenia in affected males, but no demonstrable clinical abnormalities in carrier females. Through analysis of the methylation patterns of X-linked genes that display restriction fragment length polymorphisms (RFLPs), we studied the pattern of X-chromosome inactivation in various cell populations from female relatives of patients with WAS. The peripheral blood T cells, granulocytes, and B cells of eight obligate WAS carriers were found to display specific patterns of X-chromosome inactivation clearly different from these of normal controls. Thus, carriers of WAS could be accurately identified using this analysis.

scholarly journals Atypical presentation of Wiskott-Aldrich syndrome: diagnosis in two unrelated males based on studies of maternal T cell X chromosome inactivation [see comments]

Blood ◽  
1990 ◽  
Vol 75 (12) ◽  
pp. 2369-2374 ◽  
Author(s):  
JM Puck ◽  
KA Siminovitch ◽  
M Poncz ◽  
CR Greenberg ◽  
M Rottem ◽  
...  
Keyword(s):  
T Cell ◽  
X Chromosome ◽  
Hereditary Disease ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Negative Family History ◽  
Wiskott Aldrich Syndrome ◽  
Inactivation Pattern ◽  
Skewed X Chromosome Inactivation ◽  
Cell Defect

Abstract Congenital thrombocytopenia may occur in isolation or accompanied by eczema and immunodeficiency, as part of the X-linked hereditary Wiskott- Aldrich syndrome (WAS). Because the clinical and immunologic picture of WAS is variable, particularly early in life, definite diagnosis cannot always be made in cases with a negative family history. Two unrelated males with sporadic congenital thrombocytopenia had only questionable immunologic abnormalities as infants, making them clinically indistinguishable from cases of isolated thrombocytopenia, although one developed episodic neutropenia and the other began to manifest a multisystem autoimmune disease at 2 years of age. Evaluation of X chromosome inactivation in the T cells of both patients' mothers showed each of these women to have the same highly skewed X chromosome inactivation pattern seen in carriers of typical familial WAS. A T-cell defect was subsequently directly demonstrated in the second patient, whose lymphocytes failed to proliferate to periodate and anti-CD43. Taken together, these data suggest the presence of T cell immunodeficiency consistent with WAS in these patients. Furthermore, their mothers were found to have a very high likelihood of being carriers, lending support to the diagnosis of a hereditary disease in these boys and making possible genetic prediction in other family members and subsequent pregnancies.

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